This research is guided by two hypotheses: (1) alterations in critical functional proteins enable the cancer phenotype and can be used for the classification of bladder cancer into groups of varying biologic aggressiveness, and (2) defining these alterations will provide markers that will be prognostic in individual patients with bladder cancer resulting in improved diagnosis, therapy and outcome. These clinically important bladder markers will be defined and developed through the following aims. Aim 1: Evaluate markers of bladder cancer for clinical relevance. Functional proteins that have demonstrated differential expression on a normal and malignant urothelium will be evaluated for utility as predictive markers of bladder cancer. Examples include (1) the integrin alpha6beta4 which mediates cellular communication with the extracellular matrix, (2) the integrins alpha2beta1 which an function as intercellular adhesion moleculs, and (3) connexin 26 which mediates intercellular communication through the formation of gap junctions. Aim 2: Identify new markers of bladder cancer. New markers will be developed for subsequent incorporation in Network protocols. Examples include the monoclonal antibody DD23 which binds to a protein expressed by bladder cancer cells but not normal urothelium, and the gene MAL which shows decreased expression in bladder cancer in comparison to normal urothelium. Aim 3: Participate in collaborative Network studies of bladder cancer. This proposal will continue ongoing collaboration with other members of the Bladder Cancer Marker Network to critically evaluate prognostic markers in bladder cancer. These specific aims will evaluate markers of bladder cancer for clinical utility and identify new markers for vigorous evaluation through Network protocols. Through this process clinically important markers of bladder cancer will be developed that improve the diagnosis and treatment of patients with this disease.